A conventional process for making 5-nitrobarbituric acid, sometimes referred to as dilituric acid, is the direct nitration of barbituric acid. The procedure is described in publications such as, for instance, Organic Synthesis, Coll. Vol. II:440-41 and J. Am. Chem. Soc. 62:590-3 (1940). In the conventional process barbituric acid is first prepared. One well-known synthesis of barbituric acid starts with the reaction of chloroacetic acid with sodium dicyanamide and esterification with absolute ethanol in the presence of sulfuric acid to form diethyl malonate which is isolated and purified by distillation. The diethyl malonate is subsequently allowed to condense with urea under basic conditions and then acidified to afford barbituric acid. Other conventional processes for preparing barbituric acid include the action of phosphorus oxychloride on malonic acid and urea as described in Compt. Rend., 87:752 (1878), the reaction of ethyl malonate and a sodium derivative of urea obtained from urea and sodium in liquid ammonia as described in U.S. Pat. No. 2,090,594, and a reaction sequence involving dissolving finely cut sodium in absolute alcohol, adding ethyl malonate, adding dry urea in hot absolute ethanol and refluxing before recovering the product as described in Organic Synthesis, Coll. Vol. II: 60-61. Other methods for preparing barbituric acid are mentioned in Organic Synthesis, Coll. Vol. II: 60-61. The barbituric acid is isolated and then nitrated with fuming or concentrated nitric acid to obtain 5-nitrobarbituric acid.
Another known process for preparing 5-nitrobarbituric acid is the oxidation of violuric acid as described in Ber., 16: 1134 (1883).
Salts of 5-nitrobarbituric acid are obtained by isolating the 5-nitrobarbituric acid and then forming the salt in water.
Although seemingly facile, the conventional processes for making 5-nitrobarbituric acid and its salts are cumbersome and unsuited for large scale production of 5-nitrobarbituric acid and salts thereof. In some conventional processes, five separate direct synthetic operations are carried out, with isolation of intermediate products and, in at least one instance, purification of an isolated intermediate product being required. For instance, the isolation and purification of 5-nitrobarbituric acid can be time consuming and difficult.
It would, therefore, be a significant advance in the art to provide a simpler and more cost-effective process for making 5-nitrobarbituric acid and salts thereof. It would be a further advance in the art to provide a process suitable for the large scale manufacture of 5-nitrobarbituric acid and salts thereof.
Such processes are disclosed and claimed herein.